Synthesis of alpha--amino-alpha, alpha&#39;- dihaloketones and process for the preparation of beta--amino acid derivatives by the use of the same

ABSTRACT

The present invention provides a commercially profitable process for producing a β-amino acid ester derivative  
     which comprises reacting an α-amino acid ester derivative with a base and a dihalomethane,  
     reacting the same with a lithium amide and an alkyllithium in succession,  
     and treating the reaction product with an acid in an alcohol.

TECHNICAL FIELD

[0001] The present invention relates to a process for producing aβ-amino acid ester derivative of value as intermediates ofpharmaceutical and agrochemical substances, particularly an opticallyactive β-amino acid ester derivative, and to a process for producing anα-amino-α′,α′-dihaloketone derivative of value as its intermediates.

BACKGROUND ART

[0002] As the standard method of producing β-amino acids from α-aminoacids, the process which comprises reacting a mixed acid anhydride of anα-amino acid with diazomethane and causing the resultingα-amino-α′-diazoketone to undergo rearrangement in an alcohol in thepresence of a metal catalyst such as silver ion (Liebigs Ann, 1995,pp.1217-1228) is known. However, this process requires the use ofdiazomethane, an explosive and highly toxic substance, for synthesizingsaid α-amino-α′-diazoketone so that it is unsuited for a commercialoperation.

[0003] As an alternative technology, there is known a process whichcomprises reducing an α-amino acid ester derivative with sodiumborohydride, mesylating the resulting alcohol, reacting the mesylatewith sodium cyanide, and hydrolyzing the resulting nitrile (Org. PrepProced Int. 1994, 26(5), 599). However, this process involves manyreaction steps and, in addition, requires the use of the highly toxiccyanide, thus being not suited for commercial exploitation.

[0004] In the above state of the art, the present invention has for itsobject to provide a commercially profitable process for synthesizingoptically active β-amino acid ester derivatives of value in thepharmaceutical and other fields, starting with readily availableoptically active α-amino acid esters.

DISCLOSURE OF THE INVENTION

[0005] Thus, the present invention is directed to a process forproducing a β-amino acid ester derivative of the following formula (4):

[0006] wherein R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, an aralkyl group containing 7 to 18carbon atoms or an aryl group containing 6 to 18 carbon atoms, R³represents an alkyl group containing 1 to 5 carbon atoms, and P¹ and P²each independently represents a hydrogen atom or an amino-protectinggroup or P¹ and P² taken together represents a phthaloyl group,excluding the case in which both P¹ and P² are hydrogen atoms,

[0007] which comprises reacting an α-amino acid ester derivative of thefollowing formula (1):

[0008] wherein R¹, P¹ and P² are as respectively defined above, R²represents an alkyl group containing 1 to 5 carbon atoms or an aralkylgroup containing 7 to 12 carbon atoms,

[0009] with a base and a dihalomethane of the following formula (2):

CH₂X¹X²  (2)

[0010] wherein X¹ and X² each independently represents a halogen atom,to synthesize an α-amino-α′,α′-dihaloketone derivative of the followingformula (3):

[0011] wherein R¹, P¹, P², X¹ and X² are as respectively defined above,

[0012] reacting this derivative with a lithium amide and an alkyllithiumin succession,

[0013] and treating the reaction product with an acid in an alcohol.

[0014] The present invention is further directed to a process forproducing an α-amino-α′,α′-dihaloketone derivative of the above generalformula (3)

[0015] which comprises reacting an α-amino acid ester derivative of theabove formula (1) with a base and a dihalomethane of the above formula(2).

[0016] In another aspect, the present invention is directed to a processfor producing a β-amino acid ester derivative of the above formula (4)

[0017] which comprises reacting an α-amino-α′,α′-dihaloketone derivativeof the above formula (3) with a lithium amide and an alkyllithium insuccession,

[0018] and treating the reaction product with an acid in an alcohol.

[0019] In a still another aspect, the present invention is directed toan α-amino-α′,α′-dihaloketone derivative of the above formula (3)

[0020] wherein R¹ is a benzyl group,

[0021] X¹ is a bromine atom,

[0022] X² is a chlorine atom or a bromine atom.

[0023] The present invention is now described in detail.

[0024] Referring to the above formulas (1), (3) and (4), R¹ represents asubstituted or unsubstituted straight-chain, branched-chain or cyclicalkyl group containing 1 to 18 carbon atoms, an aralkyl group containing7 to 18 carbon atoms, or an aryl group containing 6 to 18 carbon atoms.As specific examples, there can be mentioned benzyl, methyl, isopropyl,isobutyl, sec-butyl and phenyl, although these are not exclusivechoices. Preferred is benzyl or phenyl.

[0025] Referring to the formula (1), R² represents an alkyl groupcontaining 1 to 5 carbon atoms or an aralkyl group containing 7 to 12carbon atoms. As specific examples, there can be mentioned methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl,p-methylbenzyl, p-methoxybenzyl, p-nitrobenzyl and p-chlorobenzyl, amongothers. Preferred is methyl or ethyl.

[0026] In the formulas (1), (3) and (4), P¹ and P² each independentlyrepresents a hydrogen atom or an amino-protecting group, or P¹ and P²taken together represents a phthaloyl group; excluding the case in whichboth P¹ and P² are hydrogen atoms.

[0027] The amino-protecting group is not particularly restricted as faras it is a protecting group in routine use for the protection of anamino group. Thus, the groups mentioned in Protective Groups in OrganicSynthesis, 2nd Ed., Theodora W. Green, John Willey & Sons), 1990,pp.309-384, e.g. methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl,t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, dibenzyl,phthalimido, tosyl, benzoyl, trimethylsilyl, etc., can be employed.Preferred, among these, are carbamate-form protecting groups such as,for example, methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl andt-butyloxycarbonyl. When either one of P¹ and P² represents anamino-protecting group, the other preferably represents a hydrogen atom.When P¹ and P² taken together represents a phthaloyl group, it may alsobe regarded as a kind of amino-protecting group.

[0028] X¹ and X² in the formulas (2) and (3) each independentlyrepresents a halogen atom, i.e. a fluorine, chlorine, bromine or iodineatom. Preferred is a chlorine atom or a bromine atom. X¹ and X² may bethe same or different.

[0029] R³ in the formula (4) represents a straight-chain orbranched-chain alkyl group containing 1 to 5 carbon atoms. Preferred ismethyl, ethyl, n-propyl or the like.

[0030] The process for producing an α-amino-α′,α′-dihaloketonederivative in accordance with the present invention is now described.

[0031] Thus, an α-amino acid ester derivative of the formula (1) isreacted with a base and a dihalomethane of the formula (2) at −90° C. to50° C., preferably −10° C. to 30° C., to synthesize anα-amino-α′,α′-dihaloketone derivative of the formula (3).

[0032] The α-amino acid constituting said α-amino acid ester derivativeof the formula (1) is not particularly restricted but includesphenylalanine, alanine, valine, leucine, isoleucine and phenylglycine,among others. Preferred is phenylalanine or phenylglycine. In thepresent invention, even when an optically active amino acid is used asthe starting compound, the desired compound can be obtained withoutdecreasing in optical activity. Therefore, more preferred amino acid isL-phenylalanine or L-phenylglycine, which is optically active.

[0033] The base mentioned above is not particularly restricted butincludes alkyllithiums, alkylmagnesium halides, lithium amides, e.g.lithium diisopropylamide, lithium hexamethyldisilazide, etc., andhalomagnesium dialkylamides which can be prepared by reacting a Grignardreagent with a secondary amine, e.g. chloromagnesium diisopropylamide,bromomagnesium diisopropylamide and chloromagnesium dicyclohexylamide.These bases can be used independently or in a combination of 2 or morespecies. Preferred bases are halomagnesium dialkylamides, andparticularly preferred base is chloromagnesiumdiisopropylamide. Theamount of use of said base is 2 to 10 molar equivalents, preferably 3 to5 molar equivalents, based on the α-amino acid ester derivative.

[0034] The dihalomethane of the formula (2) is not particularlyrestricted but includes dichloromethane, dibromomethane andbromochioromethane, among others. Preferred is dibromomethane. Theamount of use of said dihalomethane is 1 to 10 molar equivalents,preferably 1 to 3 molar equivalents, based on the α-amino acid esterderivative.

[0035] The reaction solvent for use in conducting this reaction is notparticularly restricted but includes ether solvents, such as diethylether, 1,2-dimethoxyethane, t-butyl methyl ether, tetrahydrofuran, etc.;aliphatic hydrocarbon solvents, such as hexane, pentane, etc.; andaromatic hydrocarbon solvents, such as benzene, toluene and so forth.These solvents can be used independently or in a combination of 2 ormore species.

[0036] This reaction is carried out by diluting said α-amino acid esterderivative and dihalomethane with the reaction solvent, then adding thebase to the dilution at −90° C. to 50° C., preferably −10° C. to 30° C.,and stirring the mixture for 1 to 24 hours, preferably 2 to 10 hours.

[0037] The after-treatment following the reaction comprises stopping thereaction by adding the reaction mixture to diluted hydrochloric acid,diluted sulfuric acid or an aqueous solution of ammonium chloride or thelike, extracting the mixture with a suitable solvent such as ethylacetate, diethyl ether and toluene, washing the extract serially withsaturated aqueous solution of sodium hydrogencarbamate, saturatedaqueous solution of sodium chloride, water and the like, followed byconcentration and the routine purification procedure, e.g.recrystallization, column chromatography or the like, whereby theα-amino-α′,α′-dihaloketone can be isolated.

[0038] Among the α-amino-α′,α′-dihaloketone derivatives of the formula(3) which can be obtained by the above reaction, the derivatives of theformula (3) wherein R¹ represents a benzyl group, X¹ represents abromine atom and X² represents a chlorine atom or a bromine atom arenovel compounds which have not been described in the literatures.

[0039] The process for producing a β-amino acid ester derivative from anα-amino-α′,α′-dihaloketone is now described.

[0040] Thus, the α-amino-α′,α′-dihaloketone derivative of the formula(3) is reacted with a lithium amide and an alkyllithium in the ordermentioned and the reaction product is treated with an acid in an alcoholto give the objective β-amino acid ester derivative of the formula (4).In accordance with this reaction, even when theα-amino-α′,α′-dihaloketone derivative is an optically active compound,the objective compound can be produced without decreasing in opticalactivity.

[0041] The lithium amide mentioned above is not particularly restrictedbut includes lithium hexamethyldisilazide, lithium diisopropylamide andlithium dicyclohexylamide, among others. Preferred is lithiumhexamethyldisilazide or lithium diisopropylamide. The amount of use is 2to 5 molar equivalents, preferably 2 to 3 molar equivalents, based onthe α-amino-α′,α′-dihaloketone derivative.

[0042] The alkyllithium mentioned above is not particularly restrictedbut includes methyllithium, phenyllithium, n-butyllithium,sec-butyllithium, t-butyllithium, and n-hexyllithium, among others.Preferred is n-butyllithium. The amount of use is 1 to 10 molarequivalents, preferably 2 to 5 molar equivalents, relative to theα-amino-α′,α′-dihaloketone derivative.

[0043] The reaction solvent for use in conducting this reaction is notparticularly restricted but includes ether solvents, such as diethylether, 1,2-dimethoxyethane, t-butyl methyl ether, tetrahydrofuran, etc.;aliphatic hydrocarbon solvents, such as hexane, pentane, etc.; andaromatic hydrocarbon solvents, such as benzene, toluene and so forth.These can be used independently or two or more of them can be used incombination.

[0044] The alcohol mentioned above is not particularly restricted butincludes lower alcohols such as methanol, ethanol, n-propyl alcohol,etc. Preferred is methanol or ethanol. The alkyl moiety of this alcoholcorresponds to R³ in the formula (4).

[0045] The acid for use in the above treatment is not particularlyrestricted but hydrogenchloride and sulfuric acid can be mentioned aspreferred examples.

[0046] This reaction is carried out be reacting anα-amino-α′,α′-dihaloketone of the formula (2) with said lithium amide at−90° C. to 20° C., preferably −80° C. to 50° C., for 10 minutes to 180minutes, preferably 30 to 60 minutes, and then reacting it with saidalkyllithium at −90° C. to 20° C., preferably −80° C. to −50° C., for 10to 180 minutes, preferably 30 to 60 minutes, and adding the reactionmixture to an alcohol containing said acid.

[0047] The after-treatment may for example comprise adding water to stopthe reaction, extracting the mixture with a solvent such as ethylacetate, diethyl ether, toluene or the like, washing the extract withsaturated aqueous solution of sodium hydrogencarbonate, saturatedaqueous solution of sodium chloride, water and the like, followed byconcentration and isolation by the routine procedure such asrecrystallization, chromatography and/or the like, whereby the β-aminoacid ester derivative can be isolated.

[0048] As an alternative, the β-amino acid ester derivative of theformula (4) can be directly obtained by reacting an α-amino acid esterderivative of the formula (1) with a dihalomethane of the formula (2)and a base in the same manner as above to synthesize anα-amino-α′,α′-dihaloketone of the formula (3) and, without quenching thereaction, reacting it further with said lithium amide and alkyllithiumin succession, followed by said acid treatment in an alcohol.

BEST MODE FOR CARRYING OUT THE INVENTION

[0049] The following examples illustrate the present invention infurther detail without defining the scope of the invention.

EXAMPLE 1 Production of tert-butyl(S)-(1-Benzyl-3,3-dibromo-2-oxopropyl)carbamate

[0050] Under nitrogen gas, a solution of diisopropylamine (2.4 g, 21.6mmol) in tetrahydrofuran (10 mL) was added to n-butyllithium (in 1.6 Mhexane, 13.5 mL, 21.6 mmol) at 5° C. and the mixture was stirred for 30minutes (liquor A). Separately, under nitrogen gas in another vessel, asolution was prepared from methyl(S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (2.0 g, 7.2 mmol),dibromomethane (2.5 g, 14.4 mmol) and tetrahydrofuran (10 mL) and cooledto −70° C. (liquor B). To this liquor B was added said liquor A over 30minutes at −70° C., and the mixture was stirred for 30 minutes at thesame temperature and then warmed to 20° C. This reaction mixture waspoured in 25 mL of 2N-HCl for hydrolysis and, then, extracted with 10 mLof ethyl acetate. The organic layer was washed with 20 mL of water,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to recover 2.670 g of black solid. This solid wasrecrystallized from ethyl acetate/hexane to provide brown crystals oftert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (630 mg,92.2 area %, yield 19%).

[0051]¹H-NMR (400 MHz, CDCl₃) δ: 1.40 (s, 9H), 3.05 (dd, 1H), 3.17 (dd,1H), 4.91 (m, 1H), 4.98 (m, 1H), 6.00 (s, 1H), 7.13-7.36 (m, 5H).

EXAMPLE 2 Production of tert-butyl(S)-(1-Benzyl-3,3-dibromo-2-oxopropyl)carbamate

[0052] Under nitrogen gas, diisopropylamine (17.4 g, 157.5 mmol) wasadded to n-butylmagnesium chloride (1.8 mol/kg, 79.6 g, 143.2 mmol) over30 minutes at 40° C. and the mixture was further stirred for 2 hours atthe same temperature to prepare a white slurry (liquor A). Separately,under nitrogen gas in another vessel, a solution was prepared frommethyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8mmol), dibromomethane (12.45 g, 71.6 mmol) and THF (20 mL) (liquor B).To this liquor B was added said liquor A over 1 hour at an internaltemperature of about 5° C., and the reaction was further conducted for 1hour. This reaction mixture was poured in a mixture of concentratedhydrochloric acid (34.5 g), water (50 g) and ethyl acetate (100 mL) over15 minutes for hydrolysis. After phase separation, the organic layer waswashed with 2 portions of water (50 mL) and partially concentrated andthe residue was precipitated from hexane to provide white crystals oftert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate (8.709 g,95.5 area %, yield 55%).

EXAMPLE 3 Production of Benzyl(S)-(1-Benzyl-3,3-dibromo-2-oxopropyl)carbamate

[0053] Under nitrogen gas, diisopropylamine (38.8 g, 383.4 mmol) wasadded to n-butylmagnesium chloride (1.8 mol/kg, 178 g, 319.5 mmol) over30 minutes at 40° C. and the mixture was further stirred for 2 hours atthe same temperature to prepare a white slurry (liquor A). Separately,under nitrogen gas was in another vessel, a solution was prepared frommethyl (S)-2-benzyloxycarbonylamino-3-phenylpropanoate (20.0 g, 63. 9mmol), dibromomethane (22.22 g, 127.8 mmol) and THF (40 mL) (liquor B).To this liquor B was added said liquor A over 2 hours at an internaltemperature of about 5° C., and the reaction was further conducted at 5°C. for 2 hours. This reaction mixture was poured in a mixture ofconcentrated hydrochloric acid (73.3 g), water (100 g) and ethyl acetate(50 mL) over 1 hour for hydrolysis. After phase separation, the organiclayer was washed with 2 portions of water (100 mL each). The organiclayer was concentrated under reduced pressure to recover 34.38 g ofblack oil. This oil was purified by silica gel column chromatography torecover 22.34 g of yellow crude crystals. This crystal crop wasrecrystallized from ethyl acetate/hexane to provide white crystals ofbenzyl (S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate (11.99 g, 88.0area %, yield 57%).

[0054]¹H-NMR (400 MHz, CDCl₃) δ: 3.07 (dd, 1H), 3.16 (dd, 1H), 5.00 (m,1H), 5.07 (d, 2H), 5.32 (d, 1H), 5.93 (s, 1H), 7.10-7.47 (m, 10H)

EXAMPLE 4 Production of Ethyl(S)-(1-Benzyl-3,3-dibromo-2-oxopropyl)carbamate

[0055] Under nitrogen gas, diisopropylamine (9.67 g, 95.52 mmol) wasadded to n-butylmagnesium chloride (1.8 mol/kg, 44.2 g, 79.6 mmol) over30 minutes at 40° C. and the mixture was further stirred for 2 hours atthe same temperature to prepare a white slurry (liquor A). Separately,under nitrogen gas in another vessel, a solution was prepared frommethyl (S)-2-ethyloxycarbonylamino-3-phenylpropanoate (5.0 g, 19.9mmol), dichloromethane (3.38 g, 39.8 mmol) and THF (20 g) (liquor B). Tothis liquor B was added said liquor A over 1 hour at an internaltemperature of about 5° C., and the reaction was further conducted at 5°C. for 1 hour and at 20° C. for 15 hours. This reaction mixture waspoured in a mixture of concentrated hydrochloric acid (18.26 g), water(50 g) and ethyl acetate (30 mL) over 15 minutes for hydrolysis. Afterphase separation, the organic layer was washed with 2 portions of water(50 mL each) and under reduced pressure to give 6.259 g of black oil.This oil was precipitated from ethyl acetate/hexane to provide yellowcrystals of ethyl (S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate (989mg, 91.4 area %, yield 15%).

[0056]¹H-NMR (400 MHz, CDCl₃) δ: 1.21 (t, 3H), 3.04 (m, 1H), 3.21 (dd,1H), 4.09 (q, 2H), 4.95 (m, 1H), 5.14 (m, 1H), 6.05 (s, 1H), 7.10-7.42(m, 5H)

EXAMPLE 5 Production of tert-butyl(S)-(1-Benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate

[0057] Under nitrogen gas, diisopropylamine (19.92 g, 196.9 mmol) wasadded to n-butylmagnesium chloride (1.8 mol/kg, 99.4 g, 179 mmol) over30 minutes at 40° C. and the mixture was further stirred for 2 hours atthe same temperature to prepare a white slurry (liquor A). Separately,under nitrogen gas in another vessel, a solution was prepared frommethyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8mmol), bromochloromethane (9.27 g, 71.6 mmol) and THF (20 g) (liquor B).To this liquor B was added said liquor A over 1.5 hours at an internaltemperature of about 5° C., and the reaction was conducted at 5° C. for1 hour and at 20° C. for 16 hours. This reaction mixture was poured in amixture of concentrated hydrochloric acid (43.12 g), water (100 g) andethyl acetate (50 mL) over 10 minutes for hydrolysis. After phaseseparation, the organic layer was washed serially with water (100 mL)and saturated NaCl/H₂O, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to recover 20.08 g of a reddishbrown solid. This solid was recrystallized from ethyl acetate/hexane toprovide yellow crystals of tert-butyl(S)-(1-benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate (4.409 mg, 90.7area %, yield 30%, diastereomer ratio=42/58) as a mixture ofdiastereomers.

[0058]¹H-NMR (400 MHz, CDCl₃) δ: 1.39 (s, 9H), 1.41 (s, 9H), 2.92-3.30(m, 2H+2H), 4.75-5.08 (m, 2H+2H), 5.89 (s, 1H), 6.29 (s, 1H), 7.17-7.42(m, 5H+5H)

EXAMPLE 6 Production of tert-butyl(S)-(1-Benzyl-3,3-dichloro-2-oxopropyl)carbamate

[0059] Under nitrogen gas, diisopropylamine (19.92 g, 196.9 mmol) wasadded to n-butylmagnesium chloride (1.8 mol/kg, 99.4 g, 179 mmol) over30 minutes at 40° C. and the mixture was further stirred for 2 hours atthe same temperature to prepare a white slurry (liquor A). Separately,under nitrogen gas in another vessel, a solution was prepared frommethyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8mmol), dichloromethane (6.09 g, 71.6 mmol) and THF (20 g) (liquor B) Tothis liquor B was added said liquor A over 1.5 hours at an internaltemperature of about 5° C., and the reaction was conducted at 5° C. for6 hours and at 20° C. for 16 hours. This reaction mixture was poured ina mixture of concentrated hydrochloric acid (43.12 g), water (100 g) andethyl acetate (50 mL) over 10 minutes for hydrolysis. After phaseseparation, the organic layer was washed serially with water (100 mL)and saturated sodium hydrogencarbonate/H₂O, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to recover20.22 g of a reddish brown solid. This solid was recrystallized fromethyl acetate/hexane to provide yellow crystals of tert-butyl(S)-(1-benzyl-3,3-dichloro-2-oxopropyl)carbamate (3.921 g, 98.1 area %,yield 32%).

[0060]¹H-NMR (400 MHz, CDCl₃) δ: 1.40 (s, 9H), 3.02 (dd, 1H), 3.21 (dd,1H), 4.82-4.91 (m, 1H), 4.92-5.01 (m, 1H), 6.09 (s, 1H), 7.18-7.35 (m,5H)

EXAMPLE 7 Production of Benzyl(S)-(1-Phenyl-3,3-dibromo-2-oxopropyl)carbamate

[0061] Under nitrogen gas, diisopropylamine (27.9 g, 275.9 mmol) wasadded to n-butylmagnesium chloride (1.8 mol/kg, 139.4 g, 250.9 mmol)over 30 minutes at 40° C. and the mixture was further stirred for 2hours at the same temperature to prepare a white slurry (liquor A).Separately, under nitrogen gas in another vessel, a solution wasprepared from methyl (S)-2-benzyloxycarbonylamino-2-phenylpropionate(30.0 g, 50.17 mmol), dibromomethane (17.44 g, 100.3 mmol) and THF (30g) (liquor B). To this liquor B was added liquor A over 1 hour at aninternal temperature of about 5° C., and the reaction was furtherconducted at 5° C. for 1 hour. This reaction mixture was poured in amixture of concentrated hydrochloric acid (60.43 g), water (100 g) andethyl acetate (100 mL) over 30 minutes for hydrolysis. After phaseseparation, the organic layer was washed with 2 portions of water (100mL each), dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to give 25.44 g of a black oil. This oil was purifiedby silica gel column chromatography to provide a red oil of benzyl(S)-(1-phenyl-3,3-dibromo-2-oxopropyl)carbamate (17.15 g, 68.6 area %,yield 39%).

[0062]¹H-NMR (400 MHz, CDCl₃) δ: 5.08 (dd, 2H), 5.95 (bs, 2H), 7.25 (s,1H), 7.19-7.49 (m, 10H)

EXAMPLE 8 Production of tert-butyl(R)-(1-Benzyl-3,3-dibromo-2-oxopropyl)carbamate

[0063] Under nitrogen gas, diisopropylamine (21.5 g, 212.7 mmol) wasadded to n-butylmagnesium chloride (1.8 mol/kg, 104 g, 193.4 mmol) over30 minutes at 40° C. and the mixture was further stirred for 2 hours atthe same temperature to prepare a white slurry (liquor A). Separately,under nitrogen gas in another vessel, a solution was prepared frommethyl (R)-2-tert-butyloxycarbonylamino-3-phenypropanoate (purity 76.3wt. %, 14.14 g, 38.67 mmol), dibromomethane (13.44 g, 77.3 mmol) and THF(20 g) (liquor B). To this liquor B was added liquor A over 1 hour at aninternal temperature of about 5° C., and the reaction was furtherconducted at 5° C. for 1 hour. Then, this reaction mixture andconcentrated hydrochloric acid (46.6 g) were concurrently added to asolution composed of water (50 g) and ethyl acetate (100 mL) and thehydrolysis was carried out for 30 minutes, during which time thereaction system was controlled at pH 1 to 7. After phase separation, theorganic layer was washed with 2 portions of saturated sodiumchloride/H₂O (100 mL each), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give 30.6 g of a black oil. HPLCassay showed that the objective tert-butyl(R)-(1-benzyl-3,3-dibromo-2-oxo-propyl)carbamate had been produced in ayield of 61%. This crystal crop was recrystallized from ethylacetate/hexane to provide yellow crystals of tert-butyl(R)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate (9.033 g, 90.4 area %,yield 50%).

[0064] HPLC (Daicel Chiral Cell AD) analysis of the above product showedthat the optical purity was 98.6% e.e. for the crude product and 99.4%e.e. for the pure crystal.

EXAMPLE 9 Production of methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate

[0065] Under nitrogen, a solution composed of hexamethyldisilazane (1.53g, 9.5 mmol) and THF (5 mL) was added to n-butyllithium (1.6 M, 5.9 mL,9.5 mmol) at 5° C. and the mixture was stirred for 30 minutes (liquorA). Separately, under nitrogen in another vessel, a solution wasprepared from tert-butyl (S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate(2.0 g, 4.75 mmol) obtained by the procedure in Example 1 and THF (20mL) (liquor B). To liquor B was added liquor A over 10 minutes at −70°C., followed by stirring at the same temperature for 30 minutes (liquorC). Then, n-butyllithium (1.6 M, 14.8 mL, 23.75 mmol) was added dropwiseover 10 minutes at −70° C. and the whole mixture was further stirred for30 minutes. Thereafter, this liquor C was poured in a solution composedof methanol (30 mL) and concentrated sulfuric acid (1.02 g) at 5° C.and, after 30 minutes of stirring, a saturated aqueous solution ofsodium hydrogencarbonate (50 mL) was added for hydrolysis. This reactionmixture was extracted with ethyl acetate (50 mL) and the extract wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure to give 2.18 g of a yellow oil. This oil was purified by silicagel column chromatography to provide a yellow oil of methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate (633 mg, 97.5 area %,yield 44%)

[0066]¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (s, 9H), 2.47 (dd, 1H), 2.51 (dd,1H), 2.79 (dd, 1H), 2.82 (dd, 1H), 3.68 (s, 3H), 4.13 (m, 1H), 5.06 (bs,1H), 7.15-7.32 (m, 5H)

EXAMPLE 10 Production of methyl(R)-3-tert-butyloxycarbonylamino-4-phenylbutanoate

[0067] Under nitrogen, a solution composed of hexamethyldisilazane (1.38g, 8.58 mmol) and THF (5 mL) was added to n-butyllithium (1.6 M, 5.4 mL,8.58 mmol) at 5° C. and the mixture was stirred for 30 minutes (liquorA). Separately, under nitrogen gas in another vessel, a solution wasprepared from the tert-butyl(R)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate obtained by theprocedure in Example 8 (2.0 g, 4.29 mmol) and THF (10 mL) (liquor B). Toliquor B was added liquor A over 10 minutes at −70° C., followed bystirring at the same temperature for 30 minutes (liquor C). Then,n-butyllithium (1.6 M, 8.0 mL, 12.87 mmol) was added dropwise over 10minutes at −70° C. and the whole mixture was further stirred for 1 hour.This liquor C was then poured in a solution composed of methanol (10 mL)and concentrated sulfuric acid (1.26 g) at 5° C. and, after 30 minutesof stirring, water (50 mL) was added for hydrolysis. This reactionmixture was extracted with ethyl acetate (50 mL) and the extract wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure to give 2.30 g of a yellow oil. HPLC assay of the oil showedthat the objective methyl(R)-3-tert-butyloxycarbonylamino-4-phenylbutanoate had been produced ina yield of 62%. The optical purity as determined by HPLC (Daicel ChiralCell AD) was 100% e.e. for the crude product.

EXAMPLE 11 Production of methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate

[0068] Under nitrogen, t-butylmagnesium chloride (1.8 M, 2.64 mL, 4.76mmol) was added to a solution composed of tert-butyl(S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate (1.0 g, 2.38 mmol)obtained by the procedure in Example 1 and THF (10 mL) at 5° C. and themixture was stirred for 30 minutes. Then, n-butyllithium (1.6 M, 4.5 mL,7.14 mmol) was further added dropwise over 10 minutes at5° C. and thewhole mixture was stirred for another 2 hours (liquor A). This liquor Awas poured in a solution composed of methanol (10 mL) and concentratedsulfuric acid (641 mg) at 5° C. and the mixture was stirred for 30minutes. HPLC assay revealed that the objective methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate had been produced ina yield of 23%.

EXAMPLE 12 Production of methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate

[0069] Under nitrogen gas, t-butylmagnesium chloride (1.8 M, 2.64 mL,4.76 mmol) was added to solution composed of tert-butyl(S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate (1.0 g, 2.38 mmol)obtained by the procedure in Example 1 and THF (10 mL), at 5° C. and themixture was stirred for 30 minutes. Then, n-butylmagnesiumchloride (1.8M, 4.0 mL, 7.14 mmol) was further added dropwise over 10 minutes at 5°C. After the temperature had risen to 20° C., the mixture was stirredfor 16 hours (liquor A). This liquor A was added to a solution composedof methanol (10 mL) and concentrated sulfuric acid (641 mg) at 5° C.,followed by stirring for 30 minutes. HPLC assay revealed that theobjective methyl (S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate hadbeen produced in a yield of 9%.

EXAMPLE 13 Production of methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate

[0070] Under nitrogen, a solution of hexamethyldisilazane (1.16 g, 7.2mmol) in THF (5 mL) was added to n-butyllithium (1.6 M, 4.5 mL, 7.2mmol) at 5° C. and the mixture was stirred for 30 minutes (liquor A).Separately, under nitrogen gas in another vessel, a solution wasprepared from tert-butyl(S)-(1-benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate (1.25 g, 3.0 mmol)obtained by the procedure in Example 5 and THF (10 mL) (liquor B). Tothis liquor B was added liquor A over 1 minute at −70° C., and themixture was stirred at the same temperature for 30 minutes (liquor C).Then, n-butyllithium (1.6 M, 9.4 mL, 15.0 mmol) was further addeddropwise over 1 minute at −70° C., followed by stirring for 2 hours.This liquor was added to a solution composed of methanol (20 mL) andconcentrated sulfuric acid (1.76 g) at 5° C. and the mixture was stirredfor 30 minutes. HPLC analysis revealed that the objective methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate had been produced ina yield of 41%.

EXAMPLE 14 Production of methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate

[0071] Under nitrogen, a solution composed of hexamethyldisilazane (1.16g, 7.2 mmol) and THF (5 mL) was added to n-butyllithium (1.6 M, 4.5 mL,7.2 mmol) at 5° C. and the mixture was stirred for 30 minutes (liquorA). Separately, under nitrogen gas in another vessel, a solution wasprepared from the tert-butyl(S)-(1-benzyl-3,3-dichloro-2-oxopropyl)carbamate (1.02 g, 3.0 mmol)obtained by the procedure in Example 6 and THF (10 mL) (liquor B). Tothis liquor B was added liquor A over 1 minute at −70° C., and themixture was stirred at the same temperature for 30 minutes (liquor C).Then, n-butyllithium (1.6 M, 9.4 mL, 15.0 mmol) was further addeddropwise over 1 minute at −70° C., followed by stirring at the sametemperature for 1 hour. After the temperature had risen to 20° C., themixture was further stirred for 3 days. This liquor was added to asolution composed of methanol (20 mL) and concentrated sulfuric acid(1.76 g) at 5° C. and the mixture was stirred for 30 minutes. HPLC assayrevealed that the objective methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate had been produced ina yield of 4%.

EXAMPLE 15 Production of Ethyl(S)-3-Benzyloxycarbonylamino-4-phenylbutanoate

[0072] Under nitrogen, a solution composed of hexamethyldisilazane (1.25g, 7.74 mmol) and THF (10 mL) was added to n-butyllithium (1.6 M, 4.8mL, 7.74 mmol) at 5° C. and the mixture was stirred for 30 minutes(liquor A). Separately, under nitrogen gas in another vessel, a solutionwas prepared from the benzyl(S)-(1-benzyl-3,3-dibromo-2-oxopropyl)carbamate (2.0 g, 3.87 mmol)obtained by the procedure in Example 3 and THF (20 mL) (liquor B). Tothis liquor B was added liquor A over 10 minutes at −70° C., and themixture was stirred at the same temperature for 20 minutes (liquor C).Then, n-butyllithium (1.6 M, 12.1 mL, 19.35 mmol) was further addeddropwise over 30 minutes at −70° C., followed by stirring for 30minutes. The liquor C was added to a solution composed of ethanol (30mL) and concentrated sulfuric acid (1.88 g) at 5° C. and the mixture wasstirred for 30 minutes. This liquor was diluted with water (50 mL) andextracted with ethyl acetate (50 mL) The extract was washed with 50 mLof water, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to give 1.94 g of an orange-colored oil. This oil waspurified by silica gel column chromatography to provide a light-yellowoil of ethyl (S)-3-benzyloxycarbonylamino-4-phenylbutanoate (822 mg,95.1 area %, yield 59%).

[0073]¹H-NMR (400 MHz, CDCl₃) δ: 1.23 (t, 3H), 2.40-2.57 (m, 2H),2.79-3.00 (m, 2H), 4.13 (q, 2H), 4.22 (m, 1H), 5.06 (s, 2H), 5.33 (d,1H), 7.08-7.43 (m, 10 H)

EXAMPLE 16 Production of Methyl(S)-3-Benzyloxycarbonylamino-3-phenylpropionate

[0074] Under nitrogen, a solution composed of hexamethyldisilazane (9.49g, 58.8 mmol) and THF (50 mL) was added to n-butyllithium (1.6 M, 36.8mL, 58.8 mmol) at 5° C. over 30 minutes and the mixture was furtherstirred for 30 minutes (liquor A). Separately, under nitrogen gas inanother vessel, a solution was prepared from the benzyl(S)-(1-phenyl-3,3-dibromo-2-oxopropyl)carbamate (12.6 g, 19.6 mmol)obtained by the procedure in Example 7 and THF (16.2 g) (liquor B). Tothis liquor B was added liquor A over 30 minutes at −70° C., and themixture was stirred at the same temperature for 30 minutes (liquor C).Then, n-butyllithium (1.6 M, 61.3 mL, 294 mmol) was further addeddropwise over 30 minutes at −70° C., followed by stirring for 30minutes. This liquor was added to a solution composed of methanol (50mL) and concentrated sulfuric acid (11.52 g) at −70° C. After thetemperature had risen to 20° C., the mixture was stirred for 30 minutes.This reaction mixture was diluted with 100 mL of water and the organiclayer was taken and washed serially with water (50 mL), saturated sodiumhydrogencarbonate/H₂O (50 mL) and water (50 mL), and dried overanhydrous magnesium sulfate. It was then concentrated under reducedpressure to give 10.28 g of a red oil. This oil was purified by silicagel column chromatography to provide a yellow oil of methyl(S)-3-benzyloxycarbonylamino-3-phenylpropionate (2.896 g, 80.0 area %,yield 42%).

[0075]¹H-NMR (400 MHz, CDCl₃) δ: 2.75-2.94 (m, 2H), 3.58 (s, 3H), 5.08(dd, 2H), 5.27 (m, 1H), 5.80 (bs, 1H), 7.15-7.42 (m, 10 H)

EXAMPLE 17 Production of methyl(S)-3-tert-butyloxycarbonylamino-4-phenylbutanoate

[0076] Under nitrogen gas, diisopropylamine (9.06 g, 89.5 mmol) wasadded to n-butylmagnesium chloride (1.8 M, 44.8 mL, 80.6 mmol) over 30minutes at 40° C. and the mixture was further stirred at the sametemperature for 2 hours, whereby a white slurry was obtained (liquor A).Separately, under nitrogen gas in another vessel, a solution wasprepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate(5.0 g, 17.9 mmol), dibromomethane (4.67 g, 26.9 mmol) and THF (15 g)(liquor B). To this liquor B was added liquor A over 1 hour at aninternal temperature of about 5° C., and the reaction was furtherconducted for 1 hour. Then, n-butyllithium (1.6 M, 55.9 mL, 89.5 mmol)was added dropwise over 1 hour at −70° C., followed by stirring at thesame temperature for 30 minutes (liquor C). This liquor C was poured ina solution composed of methanol (50 mL) and concentrated sulfuric acid(17.5 g) at −70° C., and after the temperature had risen to 20° C., themixture was stirred for 30 minutes. HPLC assay revealed that theobjective methyl (S)-3-tert-butyloxycarbonylamino-4-phenylbutanate hadbeen produced in a yield of 25%.

INDUSTRIAL APPLICABILITY

[0077] The present invention, constituted as above, provides a processfor producing an optically active β-amino acid ester derivative startingwith a readily available optically active α-amino acid ester derivative,advantageously with good efficiency on a commercial scale and furtherprovides an intermediate of value for the production of pharmaceuticals.

1. A process for producing an α-amino-α′,α′-dihaloketone derivative ofthe following formula (3):

wherein R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, an aralkyl group containing 7 to 18carbon atoms or an aryl group containing 6 to 18 carbon atoms, P¹ and P²each independently represents a hydrogen atom or an amino-protectinggroup or P¹ and P² taken together represents a phthaloyl group,excluding the case in which both P¹ and P² are hydrogen atoms, and X¹and X² each independently represents a halogen atom, which comprisesreacting an α-amino acid ester derivative of the following formula (1):

wherein R¹, P¹ and P² are as respectively defined above, R² representsan alkyl group containing 1 to 5 carbon atoms or an aralkyl groupcontaining 7 to 12 carbon atoms with a base and a dihalomethane of thefollowing formula (2): CH₂X¹X²  (2) wherein X¹ and X² are asrespectively defined above.
 2. The process according to claim 1 whereinX¹ and X² each independently represents a chlorine atom or a bromineatom.
 3. The process according to claim 1 or 2 wherein the base is ahalomagnesium dialkylamide.
 4. The process according to claim 1 whereinthe dihalomethane of the formula (2) is dibromomethane and the base ischloromagnesium diisopropylamide.
 5. The process according to claim 1,2, 3 or 4 wherein R¹ represents benzyl or phenyl, R² represents methylor ethyl, P¹ represents t-butyloxycarbonyl, benzyloxycarbonyl,methyloxycarbonyl or ethyloxycarbonyl, and P² represents hydrogen. 6.The process according to claim 1, 2, 3, 4 or 5 wherein the α-amino acidester derivative of the formula (1) is an optically activeL-phenylalanine derivative or an optically active L-phenylglycinederivative.
 7. A process for producing a β-amino acid ester derivativeof the following formula (4):

wherein R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, an aralkyl group containing 7 to 18carbon atoms or an aryl group containing 6 to 18 carbon atoms, R³represents an alkyl group containing 1 to 5 carbon atoms, and P¹ and P²each independently represents a hydrogen atom or an amino-protectinggroup or P¹ and P² taken together represents a phthaloyl group,excluding the case in which both P¹ and P² are hydrogen atoms, whichcomprises reacting an α-amino acid ester derivative of the followingformula (1):

wherein R¹, P¹ and P² are as respectively defined above, with a base anda dihalomethane of the following formula (2): CH₂X¹X²  (2) wherein X¹and X² each independently represents a halogen atom, to synthesize anα-amino-α′,α′-dihaloketone derivative of the following formula (3):

wherein R¹, P¹, P², X¹ and X² are as respectively defined above,reacting this derivative with a lithium amide and an alkyllithium insuccession, and treating the reaction product with an acid in analcohol.
 8. The process-according to claim 7 wherein X¹ and X² eachindependently represents a chlorine atom or a bromine atom.
 9. Theprocess according to claim 7 or 8 wherein the base is a halomagnesiumdialkylamide.
 10. The process according to claim 7 wherein thedihalomethane of the formula (2) is dibromomethane and the base ischloromagnesium diisopropylamide.
 11. The process according to claim 7,8, 9 or 10 wherein the lithium amide is lithium hexamethyldisilazide orlithium diisopropylamide, the alkyllithium is n-butyllithium, and thealcohol is methanol or ethanol.
 12. The process according to claim 7, 8,9, 10 or 11 wherein R¹ represents benzyl or phenyl, R² represents methylor ethyl, P¹ represents t-butyloxycarbonyl, benzyloxycarbonyl,methyloxycarbonyl or ethyloxycarbonyl, and P² represents hydrogen. 13.The process according to claim 7, 8, 9, 10, 11 or 12 wherein the α-aminoacid ester derivative of the formula (1) is an optically activeL-phenylalanine derivative or an optically active L-phenylglycinederivative.
 14. A process for producing a β-amino acid ester derivativeof the following formula (4):

wherein R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 18 carbon atoms, an aralkyl group containing 7 to 18carbon atoms or an aryl group containing 6 to 18 carbon atoms, R³represents an alkyl group containing 1 to 5 carbon atoms, and P¹ and P²each independently represents a hydrogen atom or an amino-protectinggroup or P¹ and P² taken together represents a phthaloyl group,excluding the case in which both P¹ and P² are hydrogen atoms, whichcomprises reacting an α-amino-α′,α′-dihaloketone derivative of thefollowing formula (3):

wherein R¹, P¹ and P² are as respectively defined above, and X¹ and X²each independently represents a halogen atom, with a lithium amide andan alkyllithium in succession, and treating the reaction product with anacid in an alcohol.
 15. The process according to claim 14 wherein X¹ andX² each independently represents a chlorine atom or a bromine atom. 16.The process according to claim 14 or 15 wherein the lithium amide islithium hexamethyldisilazide or lithium diisopropylamide, thealkyllithium is n-butyllithium, and the alcohol is methanol or ethanol.17. The process according to claim 14, 15 or 16 wherein R¹ representsbenzyl or phenyl, P¹ represents t-butyloxycarbonyl, benzyloxycarbonyl,methyloxycarbonyl or ethyloxycarbonyl, and P² represents hydrogen. 18.The process according to claim 14, 15, 16 or 17 wherein theα-amino-α′,α′-dihaloketone derivative of the formula (3) is an opticallyactive compound.
 19. An α-amino-α′,α′-dihaloketone derivative of thefollowing general formula (3):

wherein P¹ and P² each independently represents a hydrogen atom or anamino-protecting group or P¹ and P² taken together represents aphthaloyl group, exclusive of the case in which both P¹ and P² arehydrogen atoms, R¹ represents a benzyl group, X¹ represents a bromineatom, and X² represents a chlorine atom or a bromine atom.
 20. Theα-amino-α′,α′-dihaloketone derivative according to claim 19 wherein P¹represents a t-butyloxycarbonyl, benzyloxycarbonyl, methyloxycarbonyl orethyloxycarbonyl group, and P² represents a hydrogen atom.